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ACS Nano Aug 2023Pulmonary fibrosis (PF) is a chronic lung disease characterized by excess extracellular matrix deposition and prolonged inflammation that fails to resolve and is...
Pulmonary fibrosis (PF) is a chronic lung disease characterized by excess extracellular matrix deposition and prolonged inflammation that fails to resolve and is druggable. Using resolvins and their precursors for inflammation resolution, we demonstrate a nano-enabled approach for accomplishing robust antifibrotic effects in bleomycin- or engineered nanomaterial-induced mouse and rat PF models. Targeting the lipid peroxidation-triggered NLRP3 inflammasome and NF-κB pathway in macrophages and the ROS-mediated TGF-β/Smad and S1P signaling in epithelial cells results in these potent protective effects at the ng/mL dosimetry. We further develop an inhalable biocompatible nanoparticle that encapsulates fish oil, a chosen resolvin precursor, with phosphatidylcholine and polyethylene glycol to enhance drug permeability and facilitate crossing the mucosal barrier, forming "-oilsome" (FOS). Oropharyngeal aspiration and inhalation of FOS improved the anti-inflammatory status, histological characteristics, and pulmonary function in fibrotic lungs, which was mechanistically supported by transcriptomic and proteomic analyses. Further, scale-up engineered FOS samples with the desired physicochemical properties, anti-PF efficacy, and biocompatibility were validated in different batch sizes (up to 0.2 L/batch). This study provides a practical and translatable approach to promoting inflammation resolution and PF treatment.
Topics: Rats; Mice; Animals; Pulmonary Fibrosis; Proteomics; Lung; Inflammation; Models, Animal; Disease Models, Animal
PubMed: 37535431
DOI: 10.1021/acsnano.2c10388 -
Journal of Ethnopharmacology Nov 2023Pulmonary fibrosis (PF) is a persistent and refractory illness accompanied by inflammation and fibrosis. Gracillin, a natural steroidal saponin, is one of the components...
ETHNOPHARMACOLOGICAL RELEVANCE
Pulmonary fibrosis (PF) is a persistent and refractory illness accompanied by inflammation and fibrosis. Gracillin, a natural steroidal saponin, is one of the components of Dioscorea quinqueloba which has been used in herbal medicines for treating some inflammatory diseases. Therefore, it may be a potential drug candidate for PF management.
AIM OF THE STUDY
This study aims to elucidate and verify the anti-pulmonary fibrosis effect of gracillin.
METHODS
We established an in vivo model of PF by treatment of mice with bleomycin (BLM) and an in vitro model by treatment of NIH-3T3 cells with TGF-β1. Pathological changes to the structure of lung tissue, pulmonary function, inflammatory exudation of bronchoalveolar lavage fluid (BALF) and deposition of collagen were detected in vivo, and extracellular matrix (ECM) deposition and migration were evaluated in vitro. The significance of gracillin on STAT3 phosphorylation and nuclear translocation were evaluated by western blotting, immunohistochemistry and immunofluorescence assays. The STAT3 transcriptional activity was quantified with a dual-luciferase reporter assay. Recovery experiments were performed by plasmid-directed overexpression of STAT3.
RESULTS
We found that gracillin could improve pulmonary function, reduce lung inflammation and mitigate collagen deposition to ameliorate BLM-induced PF in mice. Gracillin also suppressed TGF-β1-induced increases in ECM deposition biomarkers, including COL1A1, fibronectin, α-SMA, N-cad and vimentin, and repressed migration in NIH-3T3 cells. Additionally, gracillin suppressed the phosphorylation, nuclear translocation and transcriptional action of STAT3. Furthermore, the decreased ECM deposition and migration upon gracillin treatment were abrogated upon overexpression of STAT3 in NIH-3T3 cells.
CONCLUSIONS
Gracillin protects against PF by inhibiting the STAT3 axis, providing a safe and efficacious approach to treating PF.
Topics: Mice; Animals; Transforming Growth Factor beta1; Pulmonary Fibrosis; Lung; Collagen; Bleomycin
PubMed: 37257706
DOI: 10.1016/j.jep.2023.116704 -
The American Journal of the Medical... May 2019Idiopathic pulmonary fibrosis (IPF) is one of many clinical syndromes that are associated with aging, and is increasing in both incidence and prevalence with the rapid... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is one of many clinical syndromes that are associated with aging, and is increasing in both incidence and prevalence with the rapid rise in aging populations world-wide. There is accumulating data on how the biology of aging may influence the susceptibility to lung fibrosis in the elderly. In this review, we explore some of the known "hallmarks of aging," including telomere attrition, genomic instability, epigenetic alterations, loss of proteostasis, cellular senescence and mitochondrial dysfunction in the pathobiology of IPF. Additionally, we discuss age-associated alterations in extracellular matrix that may contribute to the development and/or progression of IPF.
Topics: Aging; Humans; Idiopathic Pulmonary Fibrosis
PubMed: 31010465
DOI: 10.1016/j.amjms.2019.02.008 -
Cellular Signalling Oct 2023Epigenetics indicates that certain phenotypes of an organism can undergo heritable changes in the absence of changes in the genetic DNA sequence. Many studies have shown... (Review)
Review
Epigenetics indicates that certain phenotypes of an organism can undergo heritable changes in the absence of changes in the genetic DNA sequence. Many studies have shown that epigenetic patterns play an important role in the lung and lung diseases. Pulmonary fibrosis (PF) is also a type of lung disease. PF is an end-stage change of a large group of lung diseases, characterized by fibroblast proliferation and massive accumulation of extracellular matrix, accompanied by inflammatory injury and histological destruction, that is, structural abnormalities caused by abnormal repair of normal alveolar tissue. It causes loss of lung function in patients with multiple complex diseases, leading to respiratory failure and subsequent death. However, current treatment options for IPF are very limited and no drugs have been shown to significantly prolong the survival of patients. Therefore, based on a systematic understanding of the disease mechanisms of PF, this review integrates the role of epigenetics in the development and course of PF, describes preventive and potential therapeutic targets for PF, and provides a theoretical basis for further exploration of the mechanisms of PF.
Topics: Humans; Pulmonary Fibrosis; Lung; Epigenesis, Genetic; Idiopathic Pulmonary Fibrosis; Fibroblasts; Fibrosis
PubMed: 37544633
DOI: 10.1016/j.cellsig.2023.110842 -
American Journal of Respiratory Cell... Sep 2016Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, represents a chronic and progressive disease with high mortality and limited therapeutic options.... (Review)
Review
Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, represents a chronic and progressive disease with high mortality and limited therapeutic options. Excessive deposition of extracellular matrix proteins results in fibrotic remodeling, alveolar destruction, and irreversible loss of lung function. Both innate and adaptive immune mechanisms contribute to fibrogenesis at several cellular and noncellular levels. Here, we summarize and discuss the role of immune cells (T cells, neutrophils, macrophages, and fibrocytes) and soluble mediators (cytokines and chemokines) involved in pulmonary fibrosis, pointing toward novel immune-based therapeutic strategies in the field.
Topics: Animals; Cytokines; Humans; Leukocytes; Models, Biological; Pulmonary Fibrosis
PubMed: 27149613
DOI: 10.1165/rcmb.2016-0121TR -
MMW Fortschritte Der Medizin Feb 2023
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Biomedicine & Pharmacotherapy =... Oct 2023Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date,...
Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date, efficient therapeutic approach for such lung diseases is lacking. N-Acetylglucosamine (NAG), an acetylated derivative of glucosamine, has been proposed as a potential protector of lung function in several types of lung diseases. The mechanism by which NAG protects against lung injury, however, remains unclear. Here, we show that NAG treatment improves pulmonary function in bleomycin (BLM)-induced lung injury model measured by flexiVent system. At early phase of lung injury, NAG treatment results in silenced immune response by targeting ARG1 macrophages activation, and, consequently, blocks KRT8 transitional stem cell in the alveolar region to stimulate PDGF Rβ fibroblasts hyperproliferation, thereby attenuating the pulmonary fibrosis. This combinational depression of immune response and extracellular matrix deposition within the lung mitigates lung injury and pulmonary fibrosis induced by BLM. Our findings provide novel insight into the protective role of NAG in lung injury.
Topics: Humans; Pulmonary Fibrosis; Lung Injury; Acetylglucosamine; Bleomycin; COVID-19
PubMed: 37633052
DOI: 10.1016/j.biopha.2023.115069 -
International Immunology Nov 2021Pulmonary fibrosis is caused by the interplay between genetic and environmental factors. Recent studies have revealed various genes associated with idiopathic pulmonary... (Review)
Review
Pulmonary fibrosis is caused by the interplay between genetic and environmental factors. Recent studies have revealed various genes associated with idiopathic pulmonary fibrosis, as well as the causative genes for familial pulmonary fibrosis. Although increased death or dysfunction of type 2 alveolar epithelial (AT2) cells has been detected in lung specimens from pulmonary fibrosis patients, it remains unclear whether and how AT2 cell death or dysfunction is responsible for the progression of pulmonary fibrosis. A recent study showed that increased AT2 cell necroptosis is the initial event in pulmonary fibrosis by analyzing patients with familial pulmonary fibrosis and an animal model that harbors the same mutation as patients. The contribution of AT2 cell necroptosis to the pathogenesis of pulmonary fibrosis has not been identified in animal model studies, which validates the effectiveness of genetic analysis of familial diseases to uncover unknown pathogeneses. Thus, further extensive genetic studies of pulmonary fibrosis along with functional studies based on genetic analysis will be crucial not only in elucidating the precise disease process but also, ultimately, in identifying novel treatment strategies for both familial and non-familial pulmonary fibrosis.
Topics: Animals; Disease Models, Animal; Idiopathic Pulmonary Fibrosis
PubMed: 34049386
DOI: 10.1093/intimm/dxab026 -
Nature Reviews. Rheumatology Sep 2018Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most... (Review)
Review
Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most notable lung complications in SSc are fibrosis and pulmonary arterial hypertension (PAH). A major challenge for the management of lung disease in SSc is detecting those patients with severe pathology and those patients who are likely to benefit from available treatments. In the past few years, strategies for managing lung fibrosis and pulmonary hypertension, including PAH, have greatly progressed. For lung fibrosis, the tools to assess risk of progression and severity of the disease have been refined. Clinical trial results support the use of immunosuppression, including high-intensity regimens with autologous stem cell transplantation. New trials are underway to test other potential therapies including treatments that are approved for use in idiopathic lung fibrosis. For PAH, identifying individuals at high risk of disease development is critical. In addition, individuals who have borderline elevation of pulmonary arterial pressure need to be appropriately managed and followed up. Many approved drugs targeting PAH are now available, and results from large-scale clinical trials provide robust evidence that various treatments for SSc-associated PAH are associated with good long-term outcomes.
Topics: Clinical Trials as Topic; Disease Progression; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Pulmonary Fibrosis; Scleroderma, Systemic; Severity of Illness Index; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome
PubMed: 30111804
DOI: 10.1038/s41584-018-0062-0 -
The International Journal of... Sep 2020Pulmonary fibrosis is characterised by excessive scarring in the lung which leads to compromised lung function, serious breathing problems and in some diseases, death.... (Review)
Review
Pulmonary fibrosis is characterised by excessive scarring in the lung which leads to compromised lung function, serious breathing problems and in some diseases, death. It includes several lung disorders with idiopathic pulmonary fibrosis (IPF) the most common and most severe. Pulmonary fibrosis is considered to be perpetuated by aberrant wound healing which leads to fibroblast accumulation, differentiation and activation, and deposition of excessive amounts of extracellular matrix (ECM) components, in particular, collagen. Recent studies have identified the importance of changes in the composition and structure of lung ECM during the development of pulmonary fibrosis and the interaction between ECM and lung cells. There is strong evidence that increased matrix stiffness induces changes in cell function including proliferation, migration, differentiation and activation. Understanding how changes in the ECM microenvironment influence cell behaviour during fibrogenesis, and the mechanisms regulating these changes, will provide insight for developing new treatments.
Topics: Animals; Collagen; Extracellular Matrix; Humans; Mechanotransduction, Cellular; Pulmonary Fibrosis
PubMed: 32668329
DOI: 10.1016/j.biocel.2020.105802